Ogerin mediated inhibition of TGF-β(1) induced myofibroblast differentiation is potentiated by acidic pH.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Idiopathic Pulmonary Fibrosis*/pathology ; Myofibroblasts*/metabolism; Benzyl Alcohols ; Cell Differentiation ; Fibroblasts/metabolism ; Fibrosis ; Humans ; Hydrogen-Ion Concentration ; Lung/pathology ; Receptors, G-Protein-Coupled/metabolism ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/pharmacology ; Triazines

Transforming growth factor beta (TGF-β) induced myofibroblast differentiation is central to the pathological scarring observed in Idiopathic Pulmonary Fibrosis (IPF) and other fibrotic diseases. Our lab has recently identified expression of GPR68 (Ovarian Cancer Gene Receptor 1, OGR1), a pH sensing G-protein coupled receptor, as a negative regulator of TGF-β induced profibrotic effects in primary human lung fibroblasts (PHLFs). We therefore hypothesized that small molecule activators of GPR68 would inhibit myofibroblast differentiation. Ogerin is a positive allosteric modulator (PAM) of GPR68, inducing a leftward shift of the dose response curve to proton induced signaling. Using PHLFs derived from patients with both non-fibrotic and IPF diagnoses, we show that Ogerin inhibits, and partially reverses TGF-β induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-β induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of Gαs pathway activation. The ability of Ogerin to inhibit both basal and TGF-β induced collagen gene transcription, and induction of Gαs signaling is enhanced at an acidic pH (pH 6.8). Similar findings were also found using fibroblasts derived from dermal, intestinal, and orbital tissue. The biological role of GPR68 in different tissues, cell types, and disease states is an evolving and emerging field. This work adds to the understanding of Gαs coupled GPCRs in fibrotic lung disease, the ability to harness the pH sensing properties of GPR68, and conserved mechanisms of fibrosis across different organ systems.
Competing Interests: The source of funding for this work does not alter our adherence to PLOS ONE policies on sharing data and materials.

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P30 ES001247 United States ES NIEHS NIH HHS; T32 ES007026 United States ES NIEHS NIH HHS; T32 HL066988 United States HL NHLBI NIH HHS

0 (Benzyl Alcohols)
0 (GPR68 protein, human)
0 (Receptors, G-Protein-Coupled)
0 (Transforming Growth Factor beta)
0 (Triazines)
0 (ogerin)

Date Created: 20220728 Date Completed: 20220801 Latest Revision: 20230727

20231215

PMC9333254

10.1371/journal.pone.0271608

35901086